The present invention relates to a novel, orally-administrable sulfonyl derivative or salt thereof which inhibits an activated coagulation factor X (which will hereinafter be abbreviated as xe2x80x9cFXaxe2x80x9d), thereby exhibiting strong anticoagulant action; and a coagulation suppressor or preventive and/or remedy for thrombosis or embolism which comprises the derivative or salt as an effective ingredient.
Exasperation of coagulation activity is an important factor for unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger""s disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reocclusion after revascularization or formation of thrombus upon extracorporeal circulation. There is accordingly a demand for an excellent anticoagulant which is excellent in dose-responsiveness, has long-lasting effects, has a low risk of hemorrhage, has less side effects and exhibits rapid and sufficient effects even by oral administration (Thrombosis Research, 68, 507-512, 1992).
Studies on anticoagulants based on various acting mechanisms suggest that a FXa inhibitor has a possibility of becoming an excellent anticoagulant. The coagulation system is a series of reactions wherein a large amount of a thrombus is produced through an amplification step due to a multi-stage enzymatic reaction and induces the formation of insoluble fibrin. In the intrinsic system, after the multi-stage reaction following the activation of a contact factor, activated Factor IX activates factor X on a phospholipid membrane in the presence of activated Factor VIII and a calcium ion, while in the extrinsic system, activated Factor VII activates Factor X in the presence of a tissue factor. In other words, the activation of Factor X into FXa in the coagulation system is an essential reaction in the formation of thrombin. Activated Factor X (FXa) in each system carries out limited proteolysis of prothrombin, thereby forming thrombin. The resulting thrombin activates the coagulation factors on the upstream side, whereby the formation of thrombin is amplified further. As described above, the coagulation system upstream of FXa is separated into intrinsic and extrinsic systems so that the inhibition of the enzyme of the coagulation system upstream of FXa does not suppress the production of FXa sufficiently, inevitably resulting in the production of thrombin. Furthermore, the coagulation occurs as a self-amplifying reaction so that the suppression of the coagulation system can be accomplished more efficiently by the inhibition of FXa which exists upstream of the thrombin than by the inhibition of the thrombin formed (Thrombosis Research, 15, 617-629(1979)).
Another merit of the FXa inhibitor is that an effective dose in a thrombus model is largely different from the dose for extending the bleeding time in an experimental hemorrhage model. From the experimental result, the FXa inhibitor is presumed to be an anticoagulant with a low risk of hemorrhage.
As a FXa inhibitor, various compounds are reported. In general, antithrombin III or antithrombin III-dependent penta-saccharide is known to have no inhibitory action against a prothrombinase complex which plays a practical role in the thrombus formation in vivo (Thrombosis Research, 68, 507-512(1992); Journal of Clinical Investigation, 71, 1383-1389(1983); Mebio, August issue, 92-97) and moreover, it does not exhibit effectiveness in oral administration. Although tick anticoagulant peptide (TAP) (Science, 248, 593-596(1990)) or antistacin (AST) (Journal of Biological Chemistry, 263, 10162-10167(1988)) isolated from a tick or leech which is a bloodsucker inhibits FXa and exhibits anti-thrombus effects on the models of from venous thrombus to arterial thrombus, it is not effective when orally administered because it is a high-molecular peptide. From such a viewpoint, a low-molecular FXa inhibitor which directly inhibits a coagulation factor without depending on antithrombin III has been developed.
An object of the present invention is to provide, as an excellent anticoagulant, a novel sulfonyl derivative or salt thereof, or a solvate thereof which has strong FXa inhibitory action, exhibits prompt, sufficient and long-lasting anti-thrombus effects even by the oral administration and has less side effects.
With the forgoing in view, the present inventors have carried out an extensive investigation on the synthesis of a novel FXa inhibitor and its pharmacological action. As a result, it has been found that a novel sulfonyl derivative or salt thereof, or solvate thereof exhibits strong FXa inhibitory activity and strong anticoagulant activity, inhibits FXa strongly, promptly and continuously by the oral administration, exhibits anti-coagulant action and antithrombus action, is highly safe and is useful as a preventive or remedy for various diseases caused by a thrombus embolus.
The present invention relates to a sulfonyl derivative represented by the below-described formula (I) or salt thereof, or a solvate thereof:
Chemical formula (I):
Q1xe2x80x94Q2xe2x80x94T1xe2x80x94Q3xe2x80x94SO2xe2x80x94QAxe2x80x83xe2x80x83(I)
[wherein, Q1 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, a saturated or unsaturated dicyclic fused ring group which may have a substituent or a saturated or unsaturated tricyclic fused ring group which may have a substituent;
Q2 represents a single bond, an oxygen atom, a sulfur atom, a linear or branched C1-6 alkylene group, a linear or branched C2-6 alkenylene group, a linear or branched C2-6 alkynylene group,
a group xe2x80x94N(R1)xe2x80x94COxe2x80x94
(in which R1 represents a hydrogen atom or an alkyl group),
a group xe2x80x94N(R2)xe2x80x94(CH2)mxe2x80x94
(in which R2 represents a hydrogen atom or an alkyl group and m stands for an integer of 0 to 6), or
a group of the following formula: 
(which represents a divalent, saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, a divalent, saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent or a divalent, saturated or unsaturated dicyclic fused ring group which may have a substituent and ←C means the bonding of the carbon atom of this group to Q1),
Q3 represents any one of the following groups: 
(in which when the carbon atom to which each of R3, R4, R5, R6, R7, R8, R10 and R11 has been bonded is not adjacent to a nitrogen atom, R3, R4, R5, R6, R7, R8, R10 and R11 each independently represents a hydrogen atom,
a hydroxyl group,
an alkyl group,
an alkoxyl group,
an alkoxyalkyl group,
an alkoxyalkyloxy group,
a hydroxyalkyl group,
a hydroxyalkyloxy group,
a hydroxyalkylcarbonyl group,
a hydroxyalkylsulfonyl group,
a formyl group,
a formylalkyl group,
a formylalkylcarbonyl group,
a formylalkylsulfonyl group,
an alkylcarbonyl group,
an alkylsulfonyl group,
an alkylcarbonylalkyl group,
an alkylsulfonylalkyl group,
a carboxyl group,
a carboxyalkyl group,
a carboxyalkyloxy group,
a carboxyalkylcarbonyl group,
a carboxyalkylsulfonyl group,
a carboxyalkylcarbonylalkyl group,
a carboxyalkylsulfonylalkyl group,
an alkoxycarbonyl group,
an alkoxycarbonylalkyl group,
an alkoxycarbonylalkyloxy group,
an alkoxycarbonylalkylcarbonyl group,
an alkoxycarbonylalkylsulfonyl group,
an amino group which may have one or two substituents,
an aminoalkyl group which may have, at the amino moiety thereof, one or two substituents,
an aminoalkyloxy group which may have, at the amino moiety thereof, one or two substituents,
an aminoalkylcarbonyl group which may have, at the amino moiety thereof, one or two substituents,
an aminoalkylcarbonyloxy group which may have, at the amino moiety thereof, one or two substituents,
an aminocarbonyl group which may have, at the amino moiety thereof, one or two substituents,
an aminocarbonylalkyl group which may have, at the amino moiety thereof, one or two substituents,
an aminocarbonylalkyloxy group which may have, at the amino moiety thereof, one or two substituents,
an alkylsulfonylaminocarbonylalkyl group which may have, at the amino moiety thereof, one substituent,
an arylsulfonylaminocarbonyl group which may have, at the amino moiety thereof, one substituent,
an aminosulfonylalkyl group which may have, at the amino moiety thereof, one or two substituents,
a cyanoalkyl group,
an alkoxyalkylaminocarbonylalkyl group which may have, at the amino moiety thereof, one substituent,
an alkylcarbonyloxyalkyl group, or
a group A1xe2x80x94B1xe2x80x94 (in which A1 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and B1 represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a group xe2x80x94Oxe2x80x94(C1-6 alkylene), a group xe2x80x94COOxe2x80x94(C1-6 alkylene), a group xe2x80x94NHCOxe2x80x94 or a group xe2x80x94NHCOxe2x80x94(C1-6 alkylene),
when the carbon atom to which each of R3, R4, R5, R6, R7, R8, R10 and R11 has been bonded is adjacent to a nitrogen atom, R3, R4, R5, R6, R7, R8, R10 and R11 each independently represents
a hydrogen atom,
an alkyl group,
a hydroxyalkyl group,
a hydroxyalkylcarbonyl group,
a hydroxyalkylsulfonyl group,
a formyl group,
a formylalkyl group,
a formylalkylcarbonyl group,
a formylalkylsulfonyl group,
an alkylcarbonyl group,
an alkylsulfonyl group,
an alkylcarbonylalkyl group,
an alkylsulfonylalkyl group,
a carboxyl group,
a carboxyalkyl group,
a carboxyalkylcarbonyl group,
a carboxyalkylsulfonyl group,
a carboxyalkylcarbonylalkyl group,
a carboxyalkylsulfonylalkyl group,
an alkoxyalkyl group,
an alkoxycarbonyl group,
an alkoxycarbonylalkyl group,
an alkoxycarbonylalkylcarbonyl group,
an alkoxycarbonylalkylsulfonyl group,
an aminoalkyl group which may have, at the amino moiety thereof, one or two substituents,
an aminoalkylcarbonyl group which may have, at the amino moiety thereof, one or two substituents,
an aminocarbonyl group which may have, at the amino moiety thereof, one or two substituents,
an aminocarbonylalkyl group which may have, at the amino moiety thereof, one or two substituents
an alkylsulfonylaminocarbonylalkyl group which may have, at the amino moiety thereof, one substituent,
an arylsulfonylaminocarbonyl group which may have, at the amino moiety thereof, one substituent,
an aminosulfonylalkyl group which may have, at the amino moiety thereof, one or two substituents,
a cyanoalkyl group,
an alkoxyalkylaminocarbonylalkyl group which may have, at the amino moiety thereof, one substituent,
an alkylcarbonyloxyalkyl, or
a group A2xe2x80x94B2xe2x80x94 (in which A2 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, and B2 represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a group xe2x80x94Oxe2x80x94(C1-6 alkylene), a group xe2x80x94COOxe2x80x94(C1-6 alkylene), a group xe2x80x94NHCOxe2x80x94 or a group xe2x80x94NHCOxe2x80x94(C1-6 alkylene group),
each of R3 and R4, R5 and R6, R7 and R8, and R10 and R11 may be coupled together with a carbon atom which constitutes the ring and represent a saturated or unsaturated 5- to 7-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, R9 and R12 each independently represents:
a hydrogen atom,
an alkyl group,
a hydroxyalkyl group,
a hydroxyalkylcarbonyl group,
a hydroxyalkylsulfonyl group,
an alkoxyl group,
an alkoxyalkyl group,
an alkoxyalkylcarbonyl group,
an alkoxyalkylsulfonyl group,
a formyl group,
a formylalkyl group,
a formylalkylcarbonyl group,
a formylalkylsulfonyl group,
an alkylcarbonyl group,
an alkylcarbonylalkyl group,
an alkylsulfonyl group,
an alkylsulfonylalkyl group,
a carboxyalkyl group,
a carboxyalkylcarbonyl group,
a carboxyalkylsulfonyl group,
a carboxyalkylcarbonylalkyl group,
a carboxyalkylsulfonylalkyl group,
an alkoxycarbonyl group,
an alkoxycarbonylalkyl group,
an alkoxycarbonylalkylcarbonyl group,
an alkoxycarbonylalkylsulfonyl group,
an amino group which may have one or two substituents,
an aminoalkyl group which may have, at the amino moiety thereof, one or two substituents
an aminoalkyloxy group which may have, at the amino moiety thereof, one or two substituents,
an aminoalkylcarbonyl group which may have, at the amino moiety thereof, one or two substituents,
an aminoalkyloxycarbonyl group which may have, at the amino moiety thereof, one or two substituents,
an aminocarbonyl group which may have, at the amino moiety thereof, one or two substituents,
an aminocarbonylalkyl group which may have, at the amino moiety thereof, one or two substituents,
an aminocarbonyloxyalkyl group which may have, at the amino moiety thereof, one or two substituents,
an alkylsulfonylaminocarbonylalkyl group which may have, at the amino moiety thereof, one substituent,
an arylsulfonylaminocarbonyl group which may have, at the amino moiety thereof, one substituent,
an aminosulfonylalkyl group which may have, at the amino moiety thereof, one or two substituents,
a cyanoalkyl group,
an alkoxyalkylaminocarbonylalkyl group which may have, at the amino moiety thereof, one substituent, or
an alkylcarbonyloxyalkyl,
R9 and R7 or R8 may be coupled together with a carbon atom constituting the ring and a nitrogen atom to which R9 has been bonded and represent a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent,
R12 and R10 or R11 may be coupled together with a carbon atom constituting the ring and a nitrogen atom to which R12 has been bonded and represent a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent,
a, b, d, e and g each independently stands for an integer of 0 or 1, c stands for an integer of 0 to 3, and f, h and i each independently represents an integer of 1 to 3, with the proviso that the sum of a, b and c stands for an integer of 2 or 3, the sum of d and e stands for an integer of 0 or 1 and the sum of f, g and h stands for an integer of 3 to 5),
QA represents an arylalkenyl group which may have a substituent, a heteroarylalkenyl group which may have a substituent, a saturated or unsaturated dicyclic fused ring group which may have a substituent, a saturated or unsaturated tricyclic fused ring group which may have a substituent, a group Arxe2x80x94C(H)xe2x95x90Nxe2x80x94 (in which, Ar represents an aryl group which may have a substituent), or a group Het-C(H)xe2x95x90Nxe2x80x94 (in which, Het represents a heteroaryl group which may have a substituent), and
T1 represents a carbonyl group,
a group xe2x80x94CH(R13)xe2x80x94
(in which R13 represents a hydrogen atom, an alkyl group, a hydroxyalkyl group having the hydroxyl group which may be protected, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group which may have, at the amino moiety thereof, a substituent (protecting group)), or
a group xe2x80x94C(xe2x95x90NOR14)xe2x80x94 or xe2x80x94C(xe2x95x90Nxe2x80x94NHR14xe2x80x2)xe2x80x94
(in which R14 and R14xe2x80x2 each independently represents a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group which may have, at the amino moiety thereof, a substituent.
The present invention also provides a pharmaceutical comprising as an effective ingredient a sulfonyl derivative represented by the above-described formula (I) or salt thereof, or a solvate thereof.
The present invention also provides a pharmaceutical composition comprising a sulfonyl derivative represented by the above-described formula (I) or salt thereof, or a solvate thereof and a pharmaceutically acceptable carrier.
The present invention also provides use of a sulfonyl derivative represented by the above-described formula (I) or salt thereof, or a solvate thereof as a pharmaceutical.
The present invention also provides a method for treating diseases caused by FXa, blood coagulating diseases and various diseases due to thrombosis or embolism, which comprises administering a sulfonyl derivative represented by the above-described formula (I) or salt thereof, or a solvate thereof.